CNS Spectrums Efficacy and safety of dasotraline in adults with
www.cambridge.org/cns
Original Research
Cite this article: Grilo CM, McElroy SL, Hudson
JI, Tsai J, Navia B, Goldman R, Deng L, Kent J,
and Loebel A (2021). Efficacy and safety of
dasotraline in adults with binge-eating
disorder: a randomized, placebo-controlled,
fixed-dose clinical trial. CNS Spectrums 26(5),
481–490.
https://doi.org/10.1017/S1092852920001406
Received: 15 January 2020
Accepted: 21 April 2020
Key words:
Binge-Eating Disorder; dasotraline; dopamine
transporter; inhibitor; norepinephrine
transporter; randomized controlled trial;
obesity; weight loss
Author for correspondence:
Robert Goldman
Email: Robert.Goldman@Sunovion.com
© The Author(s), 2020. Published by Cambridge
University Press. This is an Open Access article,
distributed under the terms of the Creative
Commons Attribution licence (http://
creativecommons.org/licenses/by/4.0/), which
permits unrestricted re-use, distribution, and
reproduction in any medium, provided the
original work is properly cited.
https://doi.org/10.1017/S1092852920001406 Published online by Cambridge University Press
binge-eating disorder: a randomized, placebo-
controlled, fixed-dose clinical trial
Carlos M. Grilo1, Susan L. McElroy2,3, James I. Hudson4,5, Joyce Tsai6,
Bradford Navia6, Robert Goldman6, Ling Deng7, Justine Kent6 and Antony Loebel8
1
Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA, 2Lindner Center of HOPE, Mason,
Ohio, USA, 3Department of Psychiatry & Behavioral Neuroscience University of Cincinnati College of Medicine,
Cincinnati, Ohio, USA, 4Biological Psychiatry Laboratory McLean Hospital, Belmont, Massachusetts, USA, 5Depart-
ment of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA, 6Global Clinical Research, Sunovion
Pharmaceuticals Inc., Marlborough, Massachusetts, USA, 7Biostatistics, Sunovion Pharmaceuticals Inc., Marlbor-
ough, Massachusetts, USA, and 8Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts, USA
Abstract
Objective. The aim of this fixed-dose study was to evaluate the efficacy and safety of dasotraline
in the treatment of patients with binge-eating disorder (BED).
Methods. Patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
criteria for BED were randomized to 12 weeks of double-blind treatment with fixed doses of
dasotraline (4 and 6 mg/d), or placebo. The primary efficacy endpoint was change in number of
binge-eating (BE) days per week at week 12. Secondary efficacy endpoints included week
12 change on the BE CGI-Severity Scale (BE-CGI-S) and the Yale-Brown Obsessive–Compul-
sive Scale Modified for BE (YBOCS-BE).
Results. At week 12, treatment with dasotraline was associated with significant improvement in
number of BE days per week on the dose of 6 mg/d (N = 162) vs placebo (N = 162; 3.47 vs
2.92; P = .0045), but not 4 mg/d (N = 161; 3.21). Improvement vs placebo was observed for
dasotraline 6 and 4 mg/d, respectively, on the BE-CGI-S (effect size [ES]: 0.37 and 0.27) and on
the YBOCS-BE total score (ES: 0.43 and 0.29). The most common adverse events on dasotraline
were insomnia, dry mouth, headache, decreased appetite, nausea, and anxiety. Changes in blood
pressure and pulse were minimal.
Conclusion. Treatment with dasotraline 6 mg/d (but not 4 mg/d) was associated with signifi-
cantly greater reduction in BE days per week. Both doses of dasotraline were generally safe and
well-tolerated and resulted in global improvement on the BE-CGI-S, as well as improvement in
BE related obsessional thoughts and compulsive behaviors on the YBOCS-BE. These results
confirm the findings of a previous flexible dose study.
Introduction
Binge-eating disorder (BED) is the most common eating-disorder diagnosis, with an estimated
lifetime prevalence of approximately 2.8% in women and 1.0% in men.1–4 BED is characterized
by recurrent episodes of excessive food intake accompanied by a sense of loss of control during
the over-eating, marked distress, and feelings of shame or guilt; however, unlike bulimia nervosa,
patients with BED do not typically engage in regular weight-compensatory behaviors such as
self-induced vomiting or use of laxatives, diuretics, or enemas.5
BED typically has an onset in early adulthood, a chronic course, and is associated with a high
degree of comorbidity with other psychiatric disorders, most notably mood disorders (partic-
ularly major depressive disorder), anxiety disorders, and alcohol abuse/dependence.1,2,6 Medical
comorbidity is also common in both epidemiologic and treatment-seeking BED populations,
including obesity, hypertension, type 2 diabetes, and chronic pain conditions.1,2,6–10 Obesity
(body mass index [BMI] ≥30 kg/m2) occurs in 30% to 50% of identified cases of BED, with higher
rates observed in individuals with longer duration of illness.2,11,12
Despite the high prevalence and chronicity of BED, and high rates of psychiatric and medical
comorbidity, the majority of individuals never receive treatment specifically for BED.1,2,13
Evidence for efficacy in the treatment of BED has been reported for various classes of medication,
including selective serotonin reuptake inhibitors, anticonvulsants (topiramate and zonisamide),
and stimulant medications (eg, lisdexamfetamine dimesylate, the only drug currently approved
by the FDA).14-19 A considerable body of evidence also supports use of cognitive-behavioral and
interpersonal therapies for the treatment of BED.20,21
Dasotraline is an inhibitor of dopamine and norepinephrine transporters, with a pharma-
cokinetic profile characterized by slow absorption and a long elimination half-life (t½, 47-77
 482
hours). This results in stable plasma concentrations over 24 hours
and permits once-daily dosing.22,23 The potential therapeutic ben-
efit of dasotraline in BED, suggested by its pharmacologic profile,
has been confirmed in a rat model of binge-like eating, where
dasotraline showed a significant dose-related reduction in binge-
like consumption of chocolate, with a smaller reduction in con-
sumption of chow.24 In a prior randomized, double-blind, placebo-
controlled trial in adults with BED, treatment with flexible doses of
dasotraline, 4 to 8 mg/d was associated with significant week
12 reduction in binge-eating (BE) days per week (P < 0.001; effect
size [ES]: 0.74).25 The aim of the current study was to replicate these
findings by evaluating the efficacy and safety of two fixed doses of
dasotraline (4 and 6 mg/d) in adults with BED.
Methods
Eligibility requirements included that adults (18-55 years) met
Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition criteria for BED,5 confirmed using the Eating Disorders
Module H of the Structured Clinical Interview for DSM disorders26
and relevant behavioral items on the Eating Disorder Examination
Questionnaire (EDE-Q; eg, presence of BE and absence of weight-
compensatory behaviors).27-29 Additionally, moderate-to-severe
BED was required, based on a history of ≥2 BE days per week for
≥6 months prior to screening; and patient diary-confirmed criteria
of ≥3 BE days per week for each of the 2 weeks prior to study
baseline.
Exclusion criteria included a BMI outside the range of 18 to 45
kg/m2; lifetime history of bulimia nervosa or anorexia nervosa; and
initiation of a formal weight loss program or psychotherapy in the
3 months prior to screening. Exclusion criteria also included a
lifetime history of psychotic disorder, bipolar disorder, hypomania,
or ADHD; history of moderate-to-severe depression within 6
months prior to screening; use of antidepressants, psychostimu-
lants, or mood stabilizers within 3 months prior to screening; and a
history of substance abuse in the past 12 months. Individuals were
also excluded who reported a history of type I or type II diabetes, or
clinically significant hypertension or cardiovascular disease.
The study was approved by an institutional review board at each
study site and conducted in accordance with the International
Conference on Harmonization Guideline for Good Clinical Prac-
tice and the Declaration of Helsinki. Written informed consent was
obtained from all patients prior to initiation of study procedures.
Study design
This study was conducted at 50 centers in the United States,
between March 31, 2017 and May 16, 2018. Following a screening
period of up to 21 days, patients were randomized (1:1:1) to receive
12 weeks of double-blind, parallel-group treatment with once-
daily, fixed doses of dasotraline (4 or 6 mg), or placebo. Random-
ization was stratified on the baseline number of BE days per week
(3-4 vs. >4 per week; from review of the patient diary for the 2 weeks
before the baseline visit), and was balanced using permuted blocks.
Randomization was managed by a computer-based interactive
voice/web response system.30
Dasotraline and placebo capsules were provided in blister packs
that were identical in packaging, labeling, weight, and appearance.
The allocation sequence was concealed from both the study patient
and all study personnel. Patients randomized to dasotraline 4 mg/d
received 4 mg/d for the duration of the treatment period. Those
https://doi.org/10.1017/S1092852920001406 Published online by Cambridge University Press
C.M. Grilo et al.
randomized to dasotraline 6 mg/d were dosed with dasotraline 4
mg/d for the first 2 weeks of the treatment period and were then
increased to 6 mg/d for the remaining duration of the treatment
period. Patients who were not able to tolerate the assigned dose
were discontinued from the study.
Patients who completed 12 weeks of treatment were eligible to
enroll in a 12-month open-label extension study. Patients who did
not enter the extension study had their medication discontinued
(without taper) and participated in a 3-week medication discon-
tinuation period intended to assess potential withdrawal effects.
Concomitant medications
Use of the following medications was permitted during the double-
blind study period for insomnia: lorazepam, temazepam, eszopi-
clone, zaleplon, zolpidem, zolpidem-CR, or melatonin (not to be
taken in combination). The following medications were prohibited:
stimulants, antidepressants, anticonvulsants, and medication asso-
ciated with weight gain or weight loss, or used for the treatment of
overweight or obesity.
Efficacy assessments
The primary efficacy endpoint was mean change from baseline to
week 12 in number of BE days per week, defined as a day with at
least one BE episode. A patient diary, completed at home to serve as
a concurrent log, was used to record the number of BE episodes per
day. The diary was used as source material and reviewed by a
trained rater at each study visit to determine whether each recorded
eating episode met BE criteria. This assessment method has notable
strengths including the reduction of recall biases.28
Secondary efficacy endpoints at week 12 consisted of change
from baseline in the BE Clinical Global Impression of Severity (BE-
CGI-S) score, proportion of patients achieving 100% cessation of
BE episodes in the final 4 weeks of study participation, proportion
of patients with ≥75% reduction in BE episodes, change from
baseline in the Yale-Brown Obsessive–Compulsive Scale Modified
for BE (YBOCS-BE) total and obsession and compulsion subscale
scores,31 change from baseline in number of BE episodes/week,
change from baseline in the eating-disorder psychopathology
global score and subscale scores (restraint, eating concern, shape
concern, and weight concern) on the brief version of the Eating
Disorder Examination Questionnaire, modified (EDE-QM),32,33
and change from baseline on the Sheehan Disability Scale (SDS)
total and subscale scores (work/school, social life, and family life/
home responsibilities).34
Safety and tolerability assessments
Safety assessments included adverse events (AEs), serious adverse
events (SAEs), laboratory and electrocardiography (ECG) assess-
ments, vital signs, and weight. Suicidality was assessed with the
Columbia–Suicide Severity Rating Scale (C–SSRS).35 A monitoring
plan was implemented to detect any possible diversion or abuse of
dasotraline, or concurrent recreational use of nonstudy drugs. The
plan included monitoring of missing or lost pills, and regular urine
drug screens and breath alcohol tests. The plan also included a list
of sentinel events that, if present, required additional medical
surveillance. For patients who did not enter the extension study,
and who discontinued study medication, potential withdrawal
symptoms during the 3-week follow-up period were assessed with
the Cocaine Selective Severity Assessment (CSSA)36; the
 CNS Spectrums
Discontinuation-Emergent Signs and Symptoms (DESS) scale37;
the Hamilton Anxiety Rating Scale (HAM-A)38; and the
Montgomery-Asberg Depression Rating Scale (MADRS).39
Statistical analysis
The intent-to-treat (ITT) population was defined as all randomized
patients who received at least one dose of study drug and had at
least one postbaseline efficacy evaluation. The safety population
was defined as all randomized patients who received at least one
dose of study medication. Study centers with sample sizes of 18 or
fewer were pooled, based on geographic proximity.
The primary efficacy measure, and secondary efficacy measures
(BE-CGI-S; YBOCS-BE; number of binge episodes per week, SDS),
were analyzed using a mixed model for repeated measures
(MMRM) with fixed effects terms for treatment, visit (as a cate-
gorical variable), pooled center, baseline BE days category (strati-
fication factor), number of BE days per week at baseline, and
treatment-by-visit interaction. The proportion of patients with
100% cessation of BE episodes in the final 4-weeks of treatment
was analyzed using a logistic regression model with treatment,
baseline binge days category (stratification factor), and baseline
number of BE days per week as covariates using a last-observation-
carried-forward (LOCF) approach. One secondary efficacy variable
(EDE-QM), where only baseline and endpoint assessments were
performed, was analyzed using an analysis of covariance
(ANCOVA) model with treatment, pooled center, baseline BE days
per week (stratification) as factors, and baseline number of BE days
per week as a covariate.
To control the overall type I error rate strongly at 5% for the
primary and key secondary endpoints, a sequential testing strategy
was planned and used. Following a fixed sequence closed testing
procedure (see Supplementary Figure S1), testing only proceeded
conditional on the statistical significance of the test(s) of prior
level(s) at a two-sided 5% significance level.
Based on results from the previous flexible-dose study,25 we
assumed mean treatment differences (vs placebo) on the primary
efficacy endpoint of 0.9 and 0.8 (common SD, 1.75) for dasotraline
4 and 6 mg/d, respectively. Therefore, it was estimated that a
sample size of 96 patients per treatment group would provide at
least 85% conjunctive power to reject both null hypotheses. The
sample size was adjusted to 160 patients per treatment group based
on a projected drop-out rate of 40%.
Descriptive statistics were used for safety variables. Rank
ANCOVA was used to analyze changes in cholesterol, triglycerides,
and glucose levels from baseline.
Results
Patients and disposition
A total of 1014 patients were screened, of whom 491 were
randomized to study treatment (Figure 1); 486 patients received
at least one dose of study drug and 485 patients had at least one
postbaseline efficacy evaluation (ITT analysis population). Twelve
patients were randomized to dasotraline 6 mg/d and initially
received a 4 mg dose, but never titrated up to the 6 mg dose. Safety
analysis results were presented by randomized treatment group.
Study completion rates were 75.9% and 65.0% for the dasotraline
4 and 6 mg dose groups, respectively, and 78.9% for placebo group;
reasons for study discontinuation are summarized in Figure 1.
https://doi.org/10.1017/S1092852920001406 Published online by Cambridge University Press
483
Clinical and demographic characteristics were comparable
between treatment groups (Table 1). The overall mean age was
37.6 years; the majority of patients were white (76.3%), female
(83.9%), and obese (75.5%), with a mean BMI of 34.5 kg/m2. The
majority were not diagnosed with BED until screening despite a
mean duration of nearly 13.5 years of BE symptoms. The mean
baseline number of BE days per week was 4.2, and the mean
number of BE episodes/wk was 5.5.
Efficacy
The primary analysis showed a significant reduction from baseline
in the LS mean (SE) number of BE days per week for the 6 mg/d
dose of dasotraline vs placebo at week 12 ( 3.5 [0.1] vs 2.9 [0.1];
P = .0045; effect size [ES]: 0.35); treatment with the 4 mg/d dose of
dasotraline did not result in a significant change vs placebo ( 3.2
[0.1] vs 2.9 [0.1]; Table 2). For the 6 mg dose of dasotraline,
significantly greater reduction vs placebo in BE days per week was
evident at week 1 and was maintained through week 12 (Figure 2A).
Sensitivity analyses of the primary efficacy endpoint were per-
formed consisting of pattern mixture models (ie, placebo-based
multiple imputations and tipping point analyses per multiple
imputations with penalties), permutation test, and generalized
linear mixed model (GLMM) analysis. The results of these analyses
supported the MMRM analysis results of the primary BE days per
week outcome.
Secondary efficacy measures
Treatment with dasotraline 4 and 6 mg/d, respectively, was associ-
ated with greater reduction at week 12 in the BE-CGI-S score (with
ES of 0.27 and 0.37), and in the YBOCS-BE total score (with ES of
0.29 and 0.43; Table 2). For the BE-CGI-S and YBOCS-BE total
score, treatment group differences were evident for both dasotra-
line 4 and 6 mg/d at week 2, and at all subsequent assessment visits
(Figure 2B,C). Treatment with dasotraline 4 and 6 mg/d, respec-
tively, was associated with greater week 12 reduction compared to
placebo in the YBOCS-BE obsession subscale (with ES of 0.29 and
0.46) and in the compulsion subscale (with ES of 0.26 and 0.37;
Table 2).
The proportion of patients achieving cessation of BE episodes in
the final 4 weeks of treatment was not significantly higher for either
dose of dasotraline compared with placebo on the LOCF-endpoint
analysis (Table 2); in a post-hoc analysis of 12-week completers, the
proportion of patients achieving cessation of BE episodes in the
final 4 weeks of treatment was higher for the 6 mg/d dose of
dasotraline (P = .03; Table 2).
On additional secondary efficacy measures, treatment with
dasotraline 4 and 6 mg/d, respectively, was associated with greater
reduction at week 12 in BE episodes/wk (with ES of 0.23 and 0.25;
Table 2). A higher proportion of patients at week 12 showed ≥75%
reduction from baseline in BE episodes/wk (69.6% vs 56.2%; nom-
inal P < .011; 75.9% vs 56.2%; nominal P = .0002).
Treatment with dasotraline 4 and 6 mg/d, respectively, was
associated with greater reduction at week 12 in the SDS total score,
with ES of 0.41 and 0.34; Table 2). Treatment with dasotraline 4 and
6 mg/d, respectively, was associated with greater reduction at week
12 vs placebo in the all three subscale scores, with ES ranging from
0.27 to 0.50 and 0.25 to 0.44; Table 2). Treatment with dasotraline
4 and 6 mg/d, respectively, was also associated with greater reduc-
tion at week 12 in the EDE-QM global score, with ES of 0.49 and
0.59; Table 2). Treatment with dasotraline 4 and 6 mg/d, respec-
tively, was associated with greater LOCF-endpoint reduction at
 484 C.M. Grilo et al.

Assessed for eligibility,

N=1014

Excluded, N=523
Not meeting inclusion criteria, n=473
Lost to follow-up, n=10
Withdrew consent, n=31
Other reasons, n=9

Randomized, N=491

Dasotraline, 4 mg/d, N=162 Dasotraline, 6 mg/d, N=163 Placebo, N=166

Did not receive treatment, n=1 Did not receive treatment, n=1 Did not receive treatment, n=3

Discontinued, N=39 Discontinued, N=57 Discontinued, N=35

Adverse events, n=14 Adverse events, n=23 Adverse events, n=2
Lost to follow-up, n=12 Lost to follow-up, n=13 Lost to follow-up, n=13
Withdrew consent, n=5 Withdrew consent, n=18 Withdrew consent, n=15
Lack of efficacy, n=0 Lack of efficacy, n=0 Lack of efficacy, n=0
Other, n=8 Other, n=3 Other, n=5

Study completers, N=123 (75.9%) Study completers, N=106 (65.0%) Study completers, N=131 (78.9%)
Safety analysis population, N=161 Safety analysis population, N=162 Safety analysis population, N=163
ITT analysis population, N=161 ITT analysis population, N=162 ITT analysis population, N=162

Figure 1. Flow diagram.

Table 1. Patient Demographic and Clinical Characteristics (ITT population)

Dasotraline 4 mg/d (N = 161) Dasotraline 6 mg/d (N = 162) Placebo (N = 162)

Age, mean (SD), years 36.9 (9.6) 38.9 (9.7) 37.1 (10.2)
Female, n (%) 138 (85.7) 133 (82.1) 136 (84.0)
Race, n (%)
White 119 (73.9) 121 (74.7) 130 (80.2)
Black/African American 25 (15.5) 32 (19.8) 29 (17.9)
Asian 7 (4.3) 4 (2.5) 1 (0.6)
Other 10 (6.2) 5 (3.1) 2 (1.2)
Ethnicity, n (%)
Hispanic/Latino 31 (19.3) 26 (16.0) 28 (17.3)
Weight, kg, mean (SD) 96.9 (19.7) 96.0 (18.0) 96.9 (20.8)
BMI, kg/m2, mean (SD)a 34.8 (6.1) 34.3 (5.7) 34.5 (6.3)
Normal/Underweight (<25), n (%) 9 (5.6) 8 (4.9) 12 (7.4)
Overweight (25 to < 30), n (%) 32 (19.9) 30 (18.5) 28 (17.3)
Obesity class I (30 to <35), n (%) 41 (25.5) 48 (29.6) 42 (25.9)
Obesity class II (35 to <40), n (%) 46 (28.6) 45 (27.8) 46 (28.4)
Obesity class III (≥40), n (%) 33 (20.5) 31 (19.1) 34 (21.0)
Age, initial symptoms, mean (SD), years 23.8 (10.8) 24.1 (11.3) 24.2 (11.2)
Age, initial diagnosis, mean (SD), years 36.7 (9.7) 38.3 (10.2) 36.8 (10.4)
Binge eating days/week, mean (SD) 4.2 (1.1) 4.2 (1.1) 4.3 (1.0)
Binge eating episodes/week, mean (SD) 5.4 (3.5) 5.4 (3.0) 5.6 (2.8)
BE-CGI-S score, mean (SD) 4.5 (0.5) 4.4 (0.5) 4.4 (0.5)
YBOCS-BE total score, mean (SD) 21.6 (3.7) 21.6 (4.3) 21.9 (3.7)

Abbreviations: BMI, body mass index; BE-CGI-S, binge-eating Clinical Global Impression–Severity; ITT, intention-to-treat; SD, standard deviation; YBOCS-BE, Yale-Brown Obsessive–Compulsive
Scale Modified for Binge-eating
a
BMI categories based on NIH criteria.41

https://doi.org/10.1017/S1092852920001406 Published online by Cambridge University Press

 CNS Spectrums 485

Table 2. Primary and Secondary Efficacy Measures (ITT Population)

Dasotraline 4 Dasotraline 6 Placebo

mg (N = 161) mg (N = 162) (N = 162) Treatment Difference (vs. Placebo)
LS mean (SE) LS mean (SE) LS mean (SE) LS mean (SE) difference Effect size P valuea
Primary efficacy variable
(4 mg/6 mg) (4 mg/6 mg) (4 mg/6 mg)
Binge-eating days/week 3.2 (0.1) 3.5 (0.1) 2.9 (0.1) 0.3 (0.2)/ 0.6 (0.2) 0.19/0.35 .119/.0045
LS mean (SE) difference Effect size P value
Secondary efficacy variables LS mean (SE) LS mean (SE) LS mean (SE)
(4 mg/6 mg) (4 mg/6 mg) (4 mg/6 mg)
BE-CGI-Severity 2.1 (0.1) 2.3 (0.1) 1.8 (0.1) 0.4 (0.2)/ 0.5 (0.2) 0.27/0.37 .0256/.0025
YBOCS-BE total score 14.1 (0.7) 15.2 (0.7) 11.8 (0.7) 2.3 (1.0)/ 3.4 (1.0) 0.29/0.43 .0154/.0005
Obsession subscale score 6.7 (0.3) 7.4 (0.4) 5.6 (0.3) 1.2 (0.5)/ 1.9 (0.5) 0.29/0.46 .0151/.0002
Compulsion subscale score 7.3 (0.4) 7.8 (0.4) 6.2 (0.4) 1.1 (0.5)/ 1.5 (0.5) 0.26/0.37 .0273/.0027
EDE-QM global score (restraint,
eating concern,shape concern, 1.20 (0.12) 1.35 (0.12) 0.54 (0.12) 0.66 (0.16)/ 0.81 (0.16) 0.49/0.59 <.0001/<.0001
and weight concern)b
SDS total score 8.6 (0.55) 8.2 (0.58) 6.1 (0.55) 2.4 (0.8)/ 2.1 (0.8) 0.41/0.34 .0018/.0103
Work/school subscale score 1.9 (0.19) 1.8 (0.20) 1.3 (0.19) 0.6 (0.3)/ 0.5 (0.3) 0.30/0.25 .0225/.0643
Social life subscale score 3.5 (0.20) 3.4 (0.21) 2.4 (0.19) 1.1 (0.3)/ 1.0 (0.3) 0.50/0.44 <.0001/.0005
Family life/home subscale score 2.9 (0.18) 3.0 (0.19) 2.4 (0.18) 0.6 (0.25)/ 0.6 (0.26) 0.27/0.30 .0256/.0185
Binge-eating episodes/week 4.3 (0.2) 4.4 (0.2) 3.7 (0.2) 0.6 (0.3)/ 0.7 (0.3) 0.23/0.25 .0495/.0372
N (%) N (%) N (%) NNT (4 mg/6 mg) Odds ratio P value
c
4-week BE-cessation at EOT (ITT) 54/161 (33.5) 55/162 (34.0) 49/162 (30.2) 31/27 1.2/1.2 ns/ns
4-week BE-cessation at EOTd 1.2/1.8
47/123 (38.2) 51/106 (48.1) 45/131 (34.4) 26/8 ns/.0298
(completer)

Abbreviations: BE-CGI-S, Binge-Eating Clinical Global Impression–Severity; CI, confidence interval; EDE-QM: Eating Disorder Examination Questionnaire, modified; EOT, end of treatment; ITT,
intention-to-treat; LS, least squares; ns, not significant (P > .05); SDS, Sheehan Disability Scale; SE, standard error; YBOCS-BE, Yale-Brown Obsessive–Compulsive Scale Modified for binge-eating.
a
P values for the primary efficacy variable is based on hierarchical testing controlled for overall type I error; P values for secondary efficacy variables are nominal (exploratory) P
values.bEvaluated using Analysis of Covariance (ANCOVA at LOCF-endpoint).cProportion of patients having no binge-eating episodes in the final four study weeks was evaluated using a
logistic regression model for LOCF-endpoint sample.dThis completer analysis was post-hoc.

week 12 vs placebo in the all three EDE-QM subscale scores, with
ES ranging from 0.36 to 0.50 and 0.44 to 0.55, respectively (Table 2).
Subgroup analysis of primary endpoint
In preplanned analyses, no significant treatment-by-subgroup
interaction effects were observed in LS mean change at week
12 in BE days per week for gender, race, age group, ethnicity, or
baseline severity (≤7 vs >7 BE episodes/wk) for either dasotraline
treatment group, and for baseline BMI category for the dasotraline
4 mg/d group. A treatment interaction with respect to baseline BMI
category was observed for the dasotraline 6 mg/d group (P = .010).
The nature of the significant interaction (quantitative vs qualita-
tive) was further evaluated using the Gail and Simon test, which
indicated that the interaction was not qualitative (P = .875).
A post-hoc analysis was performed to examine the potential
impact of body weight on treatment outcome. When patients with
class III obesity (BMI ≥40 kg/m2) were excluded, the effect of
dasotraline 4 mg/d on endpoint change in BE days per week was
significant for patients in the lower weight groups (P = .037; ES:
0.28). In contrast, the 6 mg/d dose of dasotraline showed consistent
treatment effect sizes across all baseline BMI categories.
Safety
The most frequent treatment-emergent adverse events (≥10%) in
the combined dasotraline treatment groups were insomnia, dry
mouth, headache, decreased appetite, nausea, and anxiety (Table 3).
The proportion of adverse events rated as severe on placebo,
dasotraline 4 and 6 mg/d was 2.5%, 5.0%, and 9.9%, respectively;
and the proportion discontinuing due to an adverse event was 1.2%,
8.6%, and 14.1%, respectively, with discontinuations due to insom-
nia occurring in 0%, 2.5%, and 2.5%, respectively.
There were three SAEs in the dasotraline 4 mg/d group (hiatal
hernia, inguinal hernia, and palpitations); one serious event in the
dasotraline 6 mg/d group (psychotic disorder in patient treated
previously with antipsychotics for schizoaffective disorder); and
one serious event in the placebo group (cholecystitis). There were
no deaths in the study.
Five patients in the dasotraline 6 mg/d group reported
psychosis-related events: one each with hallucinations (moderate
severity; resolved on treatment; and continued in study), paranoia
(severe; resolved on treatment; and continued in study), formica-
tion (mild; not resolved; and continued in study), psychotic disor-
der (severe; categorized as an SAE [as noted above]; not resolved;
and discontinued study), and substance-induced psychotic disor-
der due to use of an illicit drug (moderate; resolved; and discon-
tinued study). No psychosis-related events occurred in the
dasotraline 4 mg/d or placebo groups, and no mania-related events
occurred in any treatment group.
In the subgroup of patients who completed the study and
discontinued study medication (dasotraline 4 mg/d, N = 41; daso-
traline 6 mg/d, N = 36; and placebo, N = 36), no signs or symptoms
of withdrawal were identified based on increased severity scores on
the CSSA, DESS, MADRS, or HAM-A during the 3-week

https://doi.org/10.1017/S1092852920001406 Published online by Cambridge University Press

 486 C.M. Grilo et al.

Base Week 1 Week 2 Week 3 Week 4 Week 6 Week 8 Week 10 Week 12

0
Dasotraline 4 mg/d (N=161)

LS Mean Change in Binge Eang Days Per Week

Dasotraline 6 mg/d (N=162)
-1 Placebo (N=162)

* P<0.05
** P<0.01
*** P<0.001
-2 ***
**

** *
**
** *
-3 *
***
*** ** *
**
-4 Week 12 effect size for dasotraline 6 mg vs. placebo: 0.35

Base Week 2 Week 4 Week 6 Week 8 Week 10 Week 12

0
Dasotraline 4 mg/d (N=161)
LS Mean Change in Binge Eang CGI-Severity

Dasotraline 6 mg/d (N=162)

Placebo (N=162)
-1 * P<0.05
**
** P<0.01
*** P<0.001
***
*** **
* *
-2 *** *** *
** **
**

-3 Week 12 effect size for dasotraline 6 mg vs. placebo: 0.37

Base Week 2 Week 4 Week 6 Week 8 Week 10 Week 12

0
Dasotraline 4 mg/d (N=161)
Dasotraline 6 mg/d (N=162)
LS Mean Change in Y-BOCS-BE

-4 Placebo (N=162)

* P<0.05
** P<0.01
*** P<0.001
-8
***

***
-12 *** **
** **
*** *
***
*** ***
-16 Week 12 effect size for dasotraline 6 mg vs. placebo: 0.43 ***

Figure 2. Least-squares mean change from baseline to week 12 in primary and secondary efficacy measures.

https://doi.org/10.1017/S1092852920001406 Published online by Cambridge University Press

 CNS Spectrums 487

Table 3. Adverse Events and Endpoint Change in Weight, BMI, Metabolic Laboratory Values and Vital Signs (Safety Population)

Dasotraline Placebo
Treatment-emergent adverse events, n (%)a 4 mg/d (N = 161) 6 mg/d (N = 162) N = 163
Patients with any adverse event 136 (84.5) 130 (80.2) 109 (66.9)
Insomniab 48 (29.8) 65 (40.1) 22 (13.5)
Dry mouth 34 (21.1) 43 (26.5) 11 (6.7)
Headache 20 (12.4) 27 (16.7) 17 (10.4)
Decreased appetite 15 (9.3) 26 (16.0) 11 (6.7)
Nausea 19 (11.8) 21 (13.0) 9 (5.5)
Anxiety 14 (8.7) 22 (13.6) 4 (2.5)
Weight decreased 14 (8.7) 12 (7.4) 2 (1.2)
Constipation 6 (3.7) 11 (6.8) 3 (1.8)
Dizziness 8 (5.0) 9 (5.6) 3 (1.8)
Weight/BMI LS Mean (SE) LS Mean (SE) LS Mean (SE)
Week 12 change in weight, kg 3.3 (0.4)* 4.0 (0.4)* +0.2 (0.4)
2
Week 12 change in BMI, kg/m 1.2 (0.1)* 1.5 (0.1)* +0.1 (0.1)
Week 12 LOCF-endpoint shift % % %
Patients with weight reduction of ≥5% and ≥7% 30.4/18.6 31.5/18.5 4.9/1.9
Patients shifting to a higher BMI category 3.1 1.2 9.2
Week 12 LOCF-endpoint change in lab values, mg/dL Median Median Median
Triglycerides 6.0 7.0 +1.0
Total cholesterol 5.0 9.5 6.0
LDL cholesterol 3.5 5.0 1.5
HDL cholesterol 1.0 2.0 3.0
Glucose 1.0 1.0 0.0
Hemoglobin A1c (%) 0.0 0.0 0.0
Week 12 LOCF-endpoint change in systolic/diastolic BP, mm Hg Mean Mean Mean
Standing 0.5/+1.5 +1.3/+1.9 1.4/ 0.3
Supine +0.3/+1.7 +1.2/+2.1 0.5/+0.2
Orthostatic 0.8/ 0.3 +0.1/ 0.2 0.9/ 0.5
Week 12 endpoint change in pulse rate, beats/min Mean Mean Mean
Standing +5.0 +7.7 +1.4
Supine +4.8 +6.2 +0.2
Orthostatic +0.2 +1.5 +1.1

Abbreviations: BMI, body mass index; BP: blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
a
Indicates any TEAEs with a reported frequency of at least 5% in any group and the incidence in at least one dasotraline treatment group is higher than placebo.bCombined insomnia (early,
middle, and late).*P < .0001 (MMRM analysis).

discontinuation period. No patients in either treatment group had
suspected or known abuse or diversion of study drug. One patient
in the placebo group had a suspected abuse of alcohol, illicit sub-
stances, over-the-counter drugs, or prescription drugs obtained
outside the study protocol.
Treatment with both doses of dasotraline were associated with a
greater mean reduction in weight and BMI compared to placebo,
with a notably high proportion of patients with a weight reduction
≥5% and ≥7% (Table 3).
There were no clinically meaningful changes in laboratory param-
eters in either the dasotraline 4 or 6 mg/d dose groups, except small
reductions in lipids (Table 3). There were no between treatment
group differences in blood pressure, heart rate, or ECG parameters.
Discussion
In this double-blind, placebo-controlled, fixed-dose, 12-week
study, involving patients with moderate-to-severe BED, dasotraline
6 mg/d significantly improved BE days per week compared to
placebo treatment (P = .0045; primary outcome); significant reduc-
tion in BE days per week was not observed for dasotraline 4 mg/d.
Dasotraline 6 and 4 mg/d treatment was associated with

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 488
improvement in BE episodes per week (ES: 0.25 and 0.23, respec-
tively) and in the BE-CGI-S, the global measure of BED severity
(ES: 0.37 and 0.27, respectively).
Dasotraline 6 and 4 mg/d treatment demonstrated clinically
meaningful improvement compared with placebo in the YBOCS-
BE total score (ES: 0.43 and 0.29, respectively). Dasotraline treat-
ment improved obsessional thoughts related to BE and ruminative
preoccupations that interfered with daily functioning (obsession
subscale), and reduced the compulsion to binge eat, increasing
patient control and ability to resist the binging urges (compulsion
subscale). Dasotraline 6 and 4 mg/d treatment also demonstrated
clinically meaningful improvement compared with placebo in the
EDE-QM scale (ES: 0.59 and 0.49, respectively), reflecting signif-
icant reductions in global eating-disorder psychopathology (cog-
nitive features including overvaluation of shape/weight, body-
image disturbance, and maladaptive restraint). Taken together,
these YBOCS-BE and EDE-QM results suggest that dasotraline,
even without the benefit of concomitant cognitive-behavioral ther-
apy, provides effective treatment for core psychopathologic distur-
bances that represent the psychological and behavioral
underpinnings of BED. Dasotraline 6 and 4 mg/d treatment
improved binge-related impairment in functioning, as assessed
by the patient-rated SDS (with ES of 0.34 and 0.41, respectively).
The findings of the current fixed dose study are consistent with
results from a previously reported flexible dose study of dasotraline
(4-8 mg/d)25 and provide further support for the efficacy of daso-
traline in the treatment of adults with moderate-to-severe BED. As
is common in fixed dose studies for psychiatric indications (includ-
ing BED),15,40 smaller effect sizes were observed for dasotraline in
the current study compared with the previous flexible dose study.25
It is also possible that the larger placebo response observed in the
current fixed-dose study, when compared with the previous daso-
traline and other flexible dose studies in this patient population,
may have contributed to the smaller effect sizes reported here.
The lifetime comorbid substance abuse/dependence rate in
patients with BED is approximately 20% to 25%.1 In the previous
flexible dose study in BED, no evidence of abuse, misuse, or diver-
sion of dasotraline was noted.25 In the current study, the lack of
diversion or abuse of dasotraline, and the lack of withdrawal symp-
toms (as assessed by increased symptom severity scores on the
CSSA, DESS, MADRS, or HAM-A), is consistent with these previous
findings. In a prior double-blind, placebo and methylphenidate-
comparator controlled human abuse liability study in recreational
stimulant users, dasotraline doses of 8 and 16 mg were indistin-
guishable from placebo across all pharmacodynamic measures asso-
ciated with abuse potential.41 Taken together, these results suggest
that dasotraline may be associated with low abuse liability.
Dasotraline 4 and 6 mg/d was generally safe and well tolerated in
this sample of BED patients. Despite use of a fixed dose design that
did not permit dose adjustment, a relatively low percentage of
adverse events were rated as severe (6.4% and 8.7%, respectively)
or resulted in discontinuation (8.7%, and 14.2%, respectively). The
most frequent treatment-emergent adverse events (≥10%) in the
combined dasotraline treatment groups were insomnia, dry mouth,
headache, decreased appetite, nausea, and anxiety. Insomnia was
the most frequent adverse event and appeared to be dose-related,
with rates of 29.8% and 40.1% on dasotraline 4 and 6 mg/d,
respectively. However, discontinuations due to insomnia were
low (2.5% for each dose).
Psychosis-related events (eg, hallucinations and paranoia)
occurred in five patients in the dasotraline 6 mg/d group. One
patient who experienced an event in association with use of an
https://doi.org/10.1017/S1092852920001406 Published online by Cambridge University Press
C.M. Grilo et al.
illicit drug, and one patient who was hospitalized for recurrence of
psychosis reported previous treatment with antipsychotics for
schizoaffective disorder. The remaining three psychosis-related
events resolved, and the patients continued assigned treatment in
the study. No psychosis-related events occurred in the dasotraline
4 mg/d or placebo groups, and no mania-related events or suicidal
behavior occurred in any treatment group.
Changes in pulse and blood pressure (supine and standing) were
generally small (pulse increase <10 bpm; blood pressure increase
<3 mm Hg) and not clinically meaningful. No clinically meaningful
effects were observed on the QTc interval or other ECG parameters.
Epidemiologic studies have reported obesity rates of 35% to 40%
in individuals with a diagnosis of BED in the community.2 A total
of 75% of patients in the current sample met NIH criteria for
obesity based on BMI criteria42 with 20% meeting class III criteria
(BMI ≥40 kg/m2). Treatment with dasotraline (4 and 6 mg/d,
combined) was associated with clinically meaningful reduction in
weight (≥5%) in 31% of patients in the total safety sample (vs 4.9%
on placebo), and in 28.3% of obese patients (classes I-III) on
dasotraline (vs 5.7% on placebo). Small but consistent reductions
were also observed on both doses of dasotraline in metabolic
parameters. Long-term studies of dasotraline are needed to deter-
mine the degree to which reduction in weight is maintained
over time.
Potential limitations of the current study include exclusion of
patients with clinically significant psychiatric or medical comor-
bidity. We note the potential limitation inherent in reliance on
patient reports of BE behaviors. We emphasize, however, that our
assessment method utilized patient-reported diaries as source
material and that the BE criteria and frequency were determined
by trained evaluators at each study visit. This assessment method
has notable strengths including the reduction of recall biases28 and
has been used previously in several trials as an endpoint.15,17,43
Long-term studies of dasotraline are needed to determine the
degree to which the improvements are maintained over time.
Conclusion
In this placebo-controlled trial, treatment with dasotraline 6 mg/d
(but not 4 mg/d) was associated with significantly greater reduction
in BE days per week. Treatment with the 4 and 6 mg/d doses of
dasotraline was associated with improvement in measures of over-
all illness severity, in psychological and behavioral outcomes that
constitute the core and associated psychopathology of BED, and in
BED-related functional impairment. The findings of this fixed dose
study confirm results of a previous flexible dose study, and indicate
the potential of dasotraline as an efficacious, and generally well-
tolerated treatment for individuals with moderate-to-severe BED.
Acknowledgments. The study was funded by Sunovion Pharmaceuticals Inc.
The sponsors were involved in the study design, in the collection, analysis and
interpretation of data, in the writing of the report, and in the decision to submit
the article for publication. Editorial and medical writing support was provided
Dr. Edward Schweizer of Paladin Consulting Group, and was funded by
Sunovion Pharmaceuticals Inc.
Disclosures. Carlos M. Grilo reports, in the past 12 months, receiving hono-
raria for lectures delivered for CME-related activities and plenaries and lectures
at professional academic conferences and reports royalties from academic
books published by Guilford Press and Taylor & Francis Publishers. Beyond
12 months, CMG reports having received consultant fees from Shire and
Sunovion Pharmaceuticals and honoraria for CME-related lectures and for
 CNS Spectrums
lectures delivered at grand rounds and professional academic conferences
nationally and internationally. Susan L. McElroy has been a consultant to or
member of the scientific advisory board of Avanir, Bracket, F. Hoffmann-La
Roche Ltd., MedAvante, Mitsubishi Tanabe Pharma Corporation, Myriad,
Naurex, Novo Nordisk, Shire, and Sunovion. She has also been a principal or
co-investigator on studies sponsored by Alkermes, Allergan, Avanir, Azevan
Pharmaceuticals, Forest, Marriott Foundation, Medibio, Myriad, National
Institute of Mental Health, Naurex, Neurocrine, Novo Nordisk, Shire, Suno-
vion, and Takeda Pharmaceutical Company Limited. She is also an inventor on
United States Patent No. 6,323,236 B2, Use of Sulfamate Derivatives for Treat-
ing Impulse Control Disorders, and along with the patent’s assignee, University
of Cincinnati, Cincinnati, Ohio, has received payments from Johnson & John-
son, which has exclusive rights under the patent. J.I. Hudson has received grant
support from Shire and Sunovion, and has received consulting fees from
diaMentis, Iadorsia, Shire, and Sunovion. Joyce Tsai, Bradford Navia, Ling
Deng, Justine Kent, Robert Goldman, and Antony Loebel are employees of
Sunovion Pharmaceuticals, Inc.
Supplementary Materials. To view supplementary material for this article,
please visit http://dx.doi.org/10.1017/S1092852920001406.
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